ES2229355T3 - Procedimiento para la fabricacion de complejos medicamentosos. - Google Patents

Procedimiento para la fabricacion de complejos medicamentosos.

Info

Publication number: ES2229355T3
Authority: ES; Spain
Prior art keywords: compound; gly; polyalcohol; solution; spacer
Prior art date: 1996-06-06
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Lifetime

Application number

ES97924326T

Other languages

English (en)

Spanish (es)

Inventor

Kazuhiro Daiichi Pharmaceutical Co. Ltd. INOUE

Hiroshi Daiichi Pharmaceutical Co. Ltd. SUSAKI

Masahiro Daiichi Pharmaceutical Co. Ltd. IKEDA

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Daiichi Pharmaceutical Co Ltd

Original Assignee

Daiichi Pharmaceutical Co Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1996-06-06

Filing date

1997-06-05

Publication date

2005-04-16

1997-06-05 Application filed by Daiichi Pharmaceutical Co Ltd filed Critical Daiichi Pharmaceutical Co Ltd

2005-04-16 Application granted granted Critical

2005-04-16 Publication of ES2229355T3 publication Critical patent/ES2229355T3/es

2017-06-05 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

238000000034 method Methods 0.000 title claims abstract description 78
238000004519 manufacturing process Methods 0.000 title claims description 11
150000001875 compounds Chemical class 0.000 claims abstract description 243
239000003814 drug Substances 0.000 claims abstract description 188
229940079593 drug Drugs 0.000 claims abstract description 179
125000006850 spacer group Chemical group 0.000 claims abstract description 91
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 75
229920001282 polysaccharide Polymers 0.000 claims abstract description 67
239000005017 polysaccharide Substances 0.000 claims abstract description 67
238000006243 chemical reaction Methods 0.000 claims abstract description 40
-1 amine salt Chemical class 0.000 claims abstract description 39
150000001413 amino acids Chemical class 0.000 claims abstract description 27
150000004676 glycans Chemical class 0.000 claims abstract 11
150000005846 sugar alcohols Polymers 0.000 claims description 152
229920002307 Dextran Polymers 0.000 claims description 59
150000003839 salts Chemical class 0.000 claims description 55
239000002246 antineoplastic agent Substances 0.000 claims description 21
239000003795 chemical substances by application Substances 0.000 claims description 21
230000008569 process Effects 0.000 claims description 21
150000002596 lactones Chemical group 0.000 claims description 20
229940034982 antineoplastic agent Drugs 0.000 claims description 13
150000001412 amines Chemical class 0.000 claims description 5
229910052783 alkali metal Inorganic materials 0.000 claims description 4
230000003110 anti-inflammatory effect Effects 0.000 claims description 3
230000002829 reductive effect Effects 0.000 abstract description 19
125000000686 lactone group Chemical group 0.000 abstract 1
238000007086 side reaction Methods 0.000 abstract 1
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 180
239000000243 solution Substances 0.000 description 173
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 159
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 116
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 114
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 112
239000000203 mixture Substances 0.000 description 96
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 87
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 78
239000012528 membrane Substances 0.000 description 75
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
ZVYVPGLRVWUPMP-FYSMJZIKSA-N exatecan Chemical compound C1C[C@H](N)C2=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC3=CC(F)=C(C)C1=C32 ZVYVPGLRVWUPMP-FYSMJZIKSA-N 0.000 description 63
150000004804 polysaccharides Chemical class 0.000 description 56
239000011780 sodium chloride Substances 0.000 description 56
230000015572 biosynthetic process Effects 0.000 description 51
238000003786 synthesis reaction Methods 0.000 description 49
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 48
239000011541 reaction mixture Substances 0.000 description 48
239000002244 precipitate Substances 0.000 description 42
239000007864 aqueous solution Substances 0.000 description 41
159000000000 sodium salts Chemical class 0.000 description 41
238000001816 cooling Methods 0.000 description 38
239000002253 acid Substances 0.000 description 37
238000000108 ultra-filtration Methods 0.000 description 37
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
206010028980 Neoplasm Diseases 0.000 description 31
239000007983 Tris buffer Substances 0.000 description 30
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 30
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 27
230000000259 anti-tumor effect Effects 0.000 description 26
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 24
239000000126 substance Substances 0.000 description 24
230000009102 absorption Effects 0.000 description 23
238000010521 absorption reaction Methods 0.000 description 23
235000001014 amino acid Nutrition 0.000 description 21
238000005119 centrifugation Methods 0.000 description 21
239000002904 solvent Substances 0.000 description 21
238000005160 1H NMR spectroscopy Methods 0.000 description 20
238000000862 absorption spectrum Methods 0.000 description 20
238000013019 agitation Methods 0.000 description 20
238000005227 gel permeation chromatography Methods 0.000 description 19
241000699670 Mus sp. Species 0.000 description 18
238000002523 gelfiltration Methods 0.000 description 18
238000003756 stirring Methods 0.000 description 18
108090000765 processed proteins & peptides Proteins 0.000 description 16
JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 16
239000000499 gel Substances 0.000 description 15
HXUVTXPOZRFMOY-NSHDSACASA-N 2-[[(2s)-2-[[2-[(2-aminoacetyl)amino]acetyl]amino]-3-phenylpropanoyl]amino]acetic acid Chemical compound NCC(=O)NCC(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 HXUVTXPOZRFMOY-NSHDSACASA-N 0.000 description 14
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
125000003277 amino group Chemical group 0.000 description 14
FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 14
239000003480 eluent Substances 0.000 description 14
AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 12
230000001613 neoplastic effect Effects 0.000 description 12
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 11
238000004458 analytical method Methods 0.000 description 11
229910052708 sodium Inorganic materials 0.000 description 11
239000011734 sodium Substances 0.000 description 11
NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 10
108010038807 Oligopeptides Proteins 0.000 description 9
102000015636 Oligopeptides Human genes 0.000 description 9
238000010586 diagram Methods 0.000 description 9
125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
238000010898 silica gel chromatography Methods 0.000 description 9
239000012279 sodium borohydride Substances 0.000 description 9
229910000033 sodium borohydride Inorganic materials 0.000 description 9
108010016626 Dipeptides Proteins 0.000 description 8
230000000118 anti-neoplastic effect Effects 0.000 description 8
239000000706 filtrate Substances 0.000 description 8
VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 8
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
230000036961 partial effect Effects 0.000 description 7
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
239000008280 blood Substances 0.000 description 6
210000004369 blood Anatomy 0.000 description 6
150000001720 carbohydrates Chemical class 0.000 description 6
238000000502 dialysis Methods 0.000 description 6
229960004679 doxorubicin Drugs 0.000 description 6
229920005862 polyol Polymers 0.000 description 6
239000008213 purified water Substances 0.000 description 6
239000012266 salt solution Substances 0.000 description 6
210000001519 tissue Anatomy 0.000 description 6
239000008351 acetate buffer Substances 0.000 description 5
239000000872 buffer Substances 0.000 description 5
239000000470 constituent Substances 0.000 description 5
230000000694 effects Effects 0.000 description 5
238000001914 filtration Methods 0.000 description 5
125000000524 functional group Chemical group 0.000 description 5
230000002757 inflammatory effect Effects 0.000 description 5
239000003960 organic solvent Substances 0.000 description 5
229920000642 polymer Polymers 0.000 description 5
239000000047 product Substances 0.000 description 5
231100000419 toxicity Toxicity 0.000 description 5
230000001988 toxicity Effects 0.000 description 5
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
230000029936 alkylation Effects 0.000 description 4
238000005804 alkylation reaction Methods 0.000 description 4
229940121363 anti-inflammatory agent Drugs 0.000 description 4
239000002260 anti-inflammatory agent Substances 0.000 description 4
238000010533 azeotropic distillation Methods 0.000 description 4
239000002585 base Substances 0.000 description 4
210000004899 c-terminal region Anatomy 0.000 description 4
239000000969 carrier Substances 0.000 description 4
210000004027 cell Anatomy 0.000 description 4
238000009826 distribution Methods 0.000 description 4
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 4
238000002347 injection Methods 0.000 description 4
239000007924 injection Substances 0.000 description 4
KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 4
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
108091005804 Peptidases Proteins 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
239000004480 active ingredient Substances 0.000 description 3
229920000615 alginic acid Polymers 0.000 description 3
239000000783 alginic acid Substances 0.000 description 3
235000010443 alginic acid Nutrition 0.000 description 3
229960001126 alginic acid Drugs 0.000 description 3
150000004781 alginic acids Chemical class 0.000 description 3
125000000217 alkyl group Chemical group 0.000 description 3
VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 3
238000009833 condensation Methods 0.000 description 3
230000005494 condensation Effects 0.000 description 3
230000018044 dehydration Effects 0.000 description 3
238000006297 dehydration reaction Methods 0.000 description 3
238000004821 distillation Methods 0.000 description 3
239000012153 distilled water Substances 0.000 description 3
230000002209 hydrophobic effect Effects 0.000 description 3
238000001990 intravenous administration Methods 0.000 description 3
239000002609 medium Substances 0.000 description 3
210000004798 organs belonging to the digestive system Anatomy 0.000 description 3
238000002360 preparation method Methods 0.000 description 3
239000000376 reactant Substances 0.000 description 3
238000011160 research Methods 0.000 description 3
239000011347 resin Substances 0.000 description 3
229920005989 resin Polymers 0.000 description 3
230000000717 retained effect Effects 0.000 description 3
ZPEARFQUCQKODL-IRXDYDNUSA-N (2s)-4-methyl-2-[[(2s)-2-[[2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]amino]-3-phenylpropanoyl]amino]pentanoic acid Chemical compound CC(C)(C)OC(=O)NCC(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=CC=C1 ZPEARFQUCQKODL-IRXDYDNUSA-N 0.000 description 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
OLCOFUDBOLQQSB-ROUUACIJSA-N 2-[[(2S)-4-methyl-2-[[(2S)-2-[[2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]amino]-3-phenylpropanoyl]amino]pentanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)CC1=CC=CC=C1 OLCOFUDBOLQQSB-ROUUACIJSA-N 0.000 description 2
WEZDRVHTDXTVLT-GJZGRUSLSA-N 2-[[(2s)-2-[[(2s)-2-[(2-aminoacetyl)amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 WEZDRVHTDXTVLT-GJZGRUSLSA-N 0.000 description 2
QMOQBVOBWVNSNO-UHFFFAOYSA-N 2-[[2-[[2-[(2-azaniumylacetyl)amino]acetyl]amino]acetyl]amino]acetate Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(O)=O QMOQBVOBWVNSNO-UHFFFAOYSA-N 0.000 description 2
STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
108010006654 Bleomycin Proteins 0.000 description 2
201000009030 Carcinoma Diseases 0.000 description 2
COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 2
PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
IGOYNRWLWHWAQO-JTQLQIEISA-N Gly-Phe-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 IGOYNRWLWHWAQO-JTQLQIEISA-N 0.000 description 2
108010009504 Gly-Phe-Leu-Gly Proteins 0.000 description 2
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
150000008575 L-amino acids Chemical class 0.000 description 2
206010058467 Lung neoplasm malignant Diseases 0.000 description 2
DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
102000035195 Peptidases Human genes 0.000 description 2
GLUBLISJVJFHQS-VIFPVBQESA-N Phe-Gly Chemical compound OC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 GLUBLISJVJFHQS-VIFPVBQESA-N 0.000 description 2
241000700159 Rattus Species 0.000 description 2
230000002411 adverse Effects 0.000 description 2
238000001838 alkalimetric titration Methods 0.000 description 2
150000001371 alpha-amino acids Chemical class 0.000 description 2
235000008206 alpha-amino acids Nutrition 0.000 description 2
150000003863 ammonium salts Chemical class 0.000 description 2
239000012298 atmosphere Substances 0.000 description 2
UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
229960001561 bleomycin Drugs 0.000 description 2
OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
238000006664 bond formation reaction Methods 0.000 description 2
201000011510 cancer Diseases 0.000 description 2
125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
238000010531 catalytic reduction reaction Methods 0.000 description 2
239000003153 chemical reaction reagent Substances 0.000 description 2
229940106681 chloroacetic acid Drugs 0.000 description 2
238000004587 chromatography analysis Methods 0.000 description 2
238000004440 column chromatography Methods 0.000 description 2
238000005520 cutting process Methods 0.000 description 2
STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
229960000975 daunorubicin Drugs 0.000 description 2
230000001419 dependent effect Effects 0.000 description 2
150000001991 dicarboxylic acids Chemical class 0.000 description 2
201000010099 disease Diseases 0.000 description 2
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
238000012377 drug delivery Methods 0.000 description 2
230000008030 elimination Effects 0.000 description 2
238000003379 elimination reaction Methods 0.000 description 2
238000005516 engineering process Methods 0.000 description 2
BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 2
108010077435 glycyl-phenylalanyl-glycine Proteins 0.000 description 2
125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
238000001727 in vivo Methods 0.000 description 2
210000004185 liver Anatomy 0.000 description 2
201000005202 lung cancer Diseases 0.000 description 2
208000020816 lung neoplasm Diseases 0.000 description 2
125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
230000014759 maintenance of location Effects 0.000 description 2
239000000463 material Substances 0.000 description 2
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
229960004857 mitomycin Drugs 0.000 description 2
210000000056 organ Anatomy 0.000 description 2
239000000825 pharmaceutical preparation Substances 0.000 description 2
230000000144 pharmacologic effect Effects 0.000 description 2
BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
150000003077 polyols Chemical class 0.000 description 2
230000035755 proliferation Effects 0.000 description 2
235000019833 protease Nutrition 0.000 description 2
238000012827 research and development Methods 0.000 description 2
239000000741 silica gel Substances 0.000 description 2
229910002027 silica gel Inorganic materials 0.000 description 2
150000003431 steroids Chemical class 0.000 description 2
238000007920 subcutaneous administration Methods 0.000 description 2
KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
238000004448 titration Methods 0.000 description 2
238000002054 transplantation Methods 0.000 description 2
ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 2
GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
RVBUZBPJAGZHSQ-UHFFFAOYSA-N 2-chlorobutanoic acid Chemical compound CCC(Cl)C(O)=O RVBUZBPJAGZHSQ-UHFFFAOYSA-N 0.000 description 1
GAWAYYRQGQZKCR-UHFFFAOYSA-N 2-chloropropionic acid Chemical compound CC(Cl)C(O)=O GAWAYYRQGQZKCR-UHFFFAOYSA-N 0.000 description 1
XEEMVPPCXNTVNP-UHFFFAOYSA-N 3-chlorobutanoic acid Chemical compound CC(Cl)CC(O)=O XEEMVPPCXNTVNP-UHFFFAOYSA-N 0.000 description 1
QEYMMOKECZBKAC-UHFFFAOYSA-N 3-chloropropanoic acid Chemical compound OC(=O)CCCl QEYMMOKECZBKAC-UHFFFAOYSA-N 0.000 description 1
NDCQPJCNZBQYAO-UHFFFAOYSA-N 4-[[3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenoxy]methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1COC1=CC=CC(C=2C3=CC=CC(=C3N=CC=2C(=O)C=2C=CC=CC=2)C(F)(F)F)=C1 NDCQPJCNZBQYAO-UHFFFAOYSA-N 0.000 description 1
IPLKGJHGWCVSOG-UHFFFAOYSA-N 4-chlorobutanoic acid Chemical compound OC(=O)CCCCl IPLKGJHGWCVSOG-UHFFFAOYSA-N 0.000 description 1
SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
201000004384 Alopecia Diseases 0.000 description 1
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 description 1
KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
229920002101 Chitin Polymers 0.000 description 1
229920001661 Chitosan Polymers 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
229920002567 Chondroitin Polymers 0.000 description 1
150000008574 D-amino acids Chemical class 0.000 description 1
229930182832 D-phenylalanine Natural products 0.000 description 1
GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 1
201000008808 Fibrosarcoma Diseases 0.000 description 1
206010061968 Gastric neoplasm Diseases 0.000 description 1
JPVGHHQGKPQYIL-KBPBESRZSA-N Gly-Phe-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 JPVGHHQGKPQYIL-KBPBESRZSA-N 0.000 description 1
239000004471 Glycine Substances 0.000 description 1
HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
229920000057 Mannan Polymers 0.000 description 1
241000699666 Mus <mouse, genus> Species 0.000 description 1
OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
229930012538 Paclitaxel Natural products 0.000 description 1
229920002230 Pectic acid Polymers 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
239000004365 Protease Substances 0.000 description 1
206010037660 Pyrexia Diseases 0.000 description 1
108091081062 Repeated sequence (DNA) Proteins 0.000 description 1
102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
239000002262 Schiff base Substances 0.000 description 1
150000004753 Schiff bases Chemical class 0.000 description 1
GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
206010047700 Vomiting Diseases 0.000 description 1
238000009825 accumulation Methods 0.000 description 1
150000008065 acid anhydrides Chemical class 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
230000009471 action Effects 0.000 description 1
235000004279 alanine Nutrition 0.000 description 1
150000001340 alkali metals Chemical class 0.000 description 1
231100000360 alopecia Toxicity 0.000 description 1
125000000539 amino acid group Chemical group 0.000 description 1
229960002684 aminocaproic acid Drugs 0.000 description 1
229950000242 ancitabine Drugs 0.000 description 1
KZOWNALBTMILAP-JBMRGDGGSA-N ancitabine hydrochloride Chemical compound Cl.N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 KZOWNALBTMILAP-JBMRGDGGSA-N 0.000 description 1
239000003242 anti bacterial agent Substances 0.000 description 1
239000012736 aqueous medium Substances 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
150000001565 benzotriazoles Chemical class 0.000 description 1
HZVKRAKZCHXKLC-INIZCTEOSA-N benzyl 2-[[(2S)-2-amino-3-phenylpropanoyl]amino]acetate Chemical compound C(C1=CC=CC=C1)OC(CNC([C@@H](N)CC1=CC=CC=C1)=O)=O HZVKRAKZCHXKLC-INIZCTEOSA-N 0.000 description 1
229940000635 beta-alanine Drugs 0.000 description 1
239000007853 buffer solution Substances 0.000 description 1
239000006227 byproduct Substances 0.000 description 1
229940127093 camptothecin Drugs 0.000 description 1
150000001718 carbodiimides Chemical class 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
230000008859 change Effects 0.000 description 1
DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 description 1
DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
229960004316 cisplatin Drugs 0.000 description 1
239000000084 colloidal system Substances 0.000 description 1
238000006482 condensation reaction Methods 0.000 description 1
239000012043 crude product Substances 0.000 description 1
231100000599 cytotoxic agent Toxicity 0.000 description 1
239000002619 cytotoxin Substances 0.000 description 1
230000034994 death Effects 0.000 description 1
231100000517 death Toxicity 0.000 description 1
230000007423 decrease Effects 0.000 description 1
229960001259 diclofenac Drugs 0.000 description 1
DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
230000001079 digestive effect Effects 0.000 description 1
230000008034 disappearance Effects 0.000 description 1
238000004090 dissolution Methods 0.000 description 1
VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
238000001035 drying Methods 0.000 description 1
230000003511 endothelial effect Effects 0.000 description 1
125000004185 ester group Chemical group 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
230000027950 fever generation Effects 0.000 description 1
229960004369 flufenamic acid Drugs 0.000 description 1
LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
229960003692 gamma aminobutyric acid Drugs 0.000 description 1
210000001035 gastrointestinal tract Anatomy 0.000 description 1
230000009036 growth inhibition Effects 0.000 description 1
150000004820 halides Chemical class 0.000 description 1
201000005787 hematologic cancer Diseases 0.000 description 1
208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
230000002439 hemostatic effect Effects 0.000 description 1
229920000669 heparin Polymers 0.000 description 1
229960002897 heparin Drugs 0.000 description 1
229920002674 hyaluronan Polymers 0.000 description 1
229960003160 hyaluronic acid Drugs 0.000 description 1
VWQWXZAWFPZJDA-CGVGKPPMSA-N hydrocortisone succinate Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COC(=O)CCC(O)=O)[C@@H]4[C@@H]3CCC2=C1 VWQWXZAWFPZJDA-CGVGKPPMSA-N 0.000 description 1
229950006240 hydrocortisone succinate Drugs 0.000 description 1
229910052739 hydrogen Inorganic materials 0.000 description 1
239000001257 hydrogen Substances 0.000 description 1
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
229960001680 ibuprofen Drugs 0.000 description 1
239000012442 inert solvent Substances 0.000 description 1
238000001802 infusion Methods 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
238000011835 investigation Methods 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
208000032839 leukemia Diseases 0.000 description 1
AIHDCSAXVMAMJH-GFBKWZILSA-N levan Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@@H]1[C@@H](O)[C@H](O)[C@](CO)(CO[C@@H]2[C@H]([C@H](O)[C@@](O)(CO)O2)O)O1 AIHDCSAXVMAMJH-GFBKWZILSA-N 0.000 description 1
238000002483 medication Methods 0.000 description 1
229940126601 medicinal product Drugs 0.000 description 1
229960003464 mefenamic acid Drugs 0.000 description 1
HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
238000011034 membrane dialysis Methods 0.000 description 1
229960000485 methotrexate Drugs 0.000 description 1
239000011259 mixed solution Substances 0.000 description 1
210000004877 mucosa Anatomy 0.000 description 1
PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
230000003472 neutralizing effect Effects 0.000 description 1
231100000956 nontoxicity Toxicity 0.000 description 1
230000008520 organization Effects 0.000 description 1
239000003002 pH adjusting agent Substances 0.000 description 1
229960001592 paclitaxel Drugs 0.000 description 1
LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
229910052697 platinum Inorganic materials 0.000 description 1
239000010318 polygalacturonic acid Substances 0.000 description 1
150000007519 polyprotic acids Polymers 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
229960005205 prednisolone Drugs 0.000 description 1
OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
230000003449 preventive effect Effects 0.000 description 1
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
229940002612 prodrug Drugs 0.000 description 1
239000000651 prodrug Substances 0.000 description 1
235000019419 proteases Nutrition 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
210000003660 reticulum Anatomy 0.000 description 1
238000012552 review Methods 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
210000000813 small intestine Anatomy 0.000 description 1
239000007787 solid Substances 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
239000001384 succinic acid Substances 0.000 description 1
HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
230000002459 sustained effect Effects 0.000 description 1
RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
238000012360 testing method Methods 0.000 description 1
YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
125000003396 thiol group Chemical group [H]S* 0.000 description 1
230000036962 time dependent Effects 0.000 description 1
PFENFDGYVLAFBR-UHFFFAOYSA-N tinoridine Chemical compound C1CC=2C(C(=O)OCC)=C(N)SC=2CN1CC1=CC=CC=C1 PFENFDGYVLAFBR-UHFFFAOYSA-N 0.000 description 1
229950010298 tinoridine Drugs 0.000 description 1
230000004614 tumor growth Effects 0.000 description 1
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
210000002700 urine Anatomy 0.000 description 1
210000003462 vein Anatomy 0.000 description 1
229960003048 vinblastine Drugs 0.000 description 1
JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
229960004528 vincristine Drugs 0.000 description 1
OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
239000002699 waste material Substances 0.000 description 1
230000004580 weight loss Effects 0.000 description 1
239000002676 xenobiotic agent Substances 0.000 description 1
229920001221 xylan Polymers 0.000 description 1
150000004823 xylans Chemical class 0.000 description 1

Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents

Landscapes

Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Chemical & Material Sciences (AREA)
Veterinary Medicine (AREA)
Medicinal Chemistry (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Epidemiology (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Organic Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Medicinal Preparation (AREA)
Peptides Or Proteins (AREA)

ES97924326T 1996-06-06 1997-06-05 Procedimiento para la fabricacion de complejos medicamentosos. Expired - Lifetime ES2229355T3 (es)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
JP14452296		1996-06-06
JP14452296		1996-06-06

Publications (1)

Publication Number	Publication Date
ES2229355T3 true ES2229355T3 (es)	2005-04-16

Family

ID=15364300

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
ES97924326T Expired - Lifetime ES2229355T3 (es)	1996-06-06	1997-06-05	Procedimiento para la fabricacion de complejos medicamentosos.

Country Status (16)

Country	Link
US (1)	US6291671B1 (de)
EP (1)	EP0955064B1 (de)
JP (1)	JP4137184B2 (de)
CN (1)	CN1227034C (de)
AT (1)	ATE273716T1 (de)
AU (1)	AU723442B2 (de)
CA (1)	CA2257233A1 (de)
DE (1)	DE69730352T2 (de)
DK (1)	DK0955064T3 (de)
EA (1)	EA001897B1 (de)
ES (1)	ES2229355T3 (de)
ID (1)	ID17243A (de)
NO (1)	NO323626B1 (de)
PT (1)	PT955064E (de)
TW (1)	TW409058B (de)
WO (1)	WO1997046261A1 (de)

Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
TW527183B (en)	1996-06-06	2003-04-11	Daiichi Seiyaku Co	Drug complex
EA003398B1 (ru) *	1998-05-22	2003-04-24	Дайити Фармасьютикал Ко., Лтд.	Лекарственный комплекс c полимерным носителем
US20030166513A1 (en) *	2000-06-29	2003-09-04	Akihiro Imura	Dds compound and process for the preparation thereof
EP1401875A4 (de) *	2001-05-04	2005-01-26	Univ Utah Res Found	Hyaluronsäure enthaltende biokonjugate: gezielte abgabe von antikrebsmitteln an krebszellen
US20030049253A1 (en) *	2001-08-08	2003-03-13	Li Frank Q.	Polymeric conjugates for delivery of MHC-recognized epitopes via peptide vaccines
US20050169883A1 (en) *	2002-05-06	2005-08-04	Prestwich Glenn D.	Preblocking with non-ha gags increases effectiveness of ha conjugated anticancer agents
US7691830B2 (en) *	2005-02-17	2010-04-06	Clive Elson	Method and composition for treatment of a mucosal tissue disorder
MX2007013725A (es)	2005-05-05	2008-04-09	Sensient Flavors Inc	Produccion de beta-glucanos y mananos.
WO2007004675A1 (ja) *	2005-07-06	2007-01-11	Seikagaku Corporation	薬剤導入光架橋ヒアルロン酸誘導体ゲル
ITPD20050242A1 (it)	2005-08-03	2007-02-04	Fidia Farmaceutici	Bioconiugati antitumorali dell'acido ialuronico o dei suoi derivati, ottenibili per coniugazione chimica diretta o indiretta, e loro impiego in campo farmaceutico
CN1973902B (zh) *	2006-12-12	2010-11-10	东北师范大学	以人参多糖为载体的抗肿瘤药物阿霉素复合物及制备方法
US9895449B2 (en)	2010-05-25	2018-02-20	Syndevrx, Inc.	Polymer-conjugated MetAP2 inhibitors, and therapeutic methods of use thereof
WO2011150022A2 (en)	2010-05-25	2011-12-01	Syndevrx, Inc.	Polymer-conjugated metap2 inhibitors, and therapeutic methods of use thereof
ES2773710T3 (es)	2012-10-11	2020-07-14	Daiichi Sankyo Co Ltd	Enlazadores para conjugados de anticuerpo - fármaco
WO2014061277A1 (ja)	2012-10-19	2014-04-24	第一三共株式会社	親水性構造を含むリンカーで結合させた抗体－薬物コンジュゲート
CA2908993C (en)	2013-04-10	2023-05-23	Syndevrx, Inc.	Metap2 inhibitors and methods of treating obesity
WO2015071841A1 (en)	2013-11-12	2015-05-21	Druggability Technologies Holdings Limited	Complexes of dabigatran and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them
AU2014371934B2 (en)	2013-12-25	2020-01-23	Daiichi Sankyo Company, Limited	Anti-TROP2 antibody-drug conjugate
IL310627B2 (en)	2014-01-31	2026-04-01	Daiichi Sankyo Co Ltd	Anti-HER2 antibody-drug conjugates, compositions containing them and uses thereof
EP3130608B1 (de)	2014-04-10	2019-09-04	Daiichi Sankyo Co., Ltd.	(anti-her2-antikörper)-arzneimittelkonjugat
KR102445502B1 (ko)	2014-04-10	2022-09-21	다이이찌 산쿄 가부시키가이샤	항her3 항체-약물 콘주게이트
CN116059395A (zh)	2015-06-29	2023-05-05	第一三共株式会社	用于选择性制造抗体-药物缀合物的方法
ES2893749T3 (es)	2015-12-10	2022-02-10	Syndevrx Inc	Derivados de fumagilol y polimorfos de los mismos
CA3239447A1 (en)	2016-01-11	2017-07-20	Syndevrx, Inc.	Treatment for tumors driven by metabolic dysfunction
US11273155B2 (en)	2016-12-12	2022-03-15	Daiichi Sankyo Company, Limited	Combination of antibody-drug conjugate and immune checkpoint inhibitor
JP6679762B2 (ja)	2017-01-17	2020-04-15	第一三共株式会社	抗ｇｐｒ２０抗体及び抗ｇｐｒ２０抗体−薬物コンジュゲート
TW202532104A (zh)	2017-05-15	2025-08-16	日商第一三共股份有限公司	抗體－藥物結合物及其用途
IL324591A (en)	2017-08-31	2026-01-01	Daiichi Sankyo Co Ltd	Improved antibody-drug conjugate production methods
CA3074208C (en)	2017-08-31	2023-10-03	Daiichi Sankyo Company, Limited	Novel method for producing antibody-drug conjugate
SG11202010496WA (en)	2018-05-18	2020-12-30	Daiichi Sankyo Co Ltd	Anti-muc1 antibody-drug conjugate
WO2020022475A1 (ja)	2018-07-27	2020-01-30	第一三共株式会社	抗体－薬物コンジュゲートの薬物部位を認識する蛋白質
CA3108044A1 (en)	2018-07-31	2020-02-06	Daiichi Sankyo Company, Limited	Treatment of metastatic brain tumor by administration of antibody-drug conjugate
JP2022512826A (ja)	2018-10-26	2022-02-07	シンデブルックス，インコーポレイティド	ＭｅｔＡＰ２阻害剤のバイオマーカーとその応用
US11555019B2 (en)	2019-07-10	2023-01-17	Cybrexa 3, Inc.	Peptide conjugates of microtubule-targeting agents as therapeutics
MX2022000449A (es)	2019-07-10	2022-04-25	Cybrexa 2 Inc	Conjugados peptídicos de citotoxinas como terapéuticos.
TW202320858A (zh)	2021-07-19	2023-06-01	美商薩諾管理公司	免疫接合物及方法
US11806405B1 (en)	2021-07-19	2023-11-07	Zeno Management, Inc.	Immunoconjugates and methods

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JPS5746920A (en) *	1980-09-03	1982-03-17	Kyosei Seiyaku Kk	Drug for digestive tract
DE3152319C2 (de)	1980-09-03	1986-05-07	Kyosei Pharmaceutical Co., Ltd., Hokkaido	Verwendung einer Lösung eines Salzes der Alginsäure zur Behandlung von Strahlenschäden und Ulcera
JPS59220197A (ja)	1983-05-30	1984-12-11	Snow Brand Milk Prod Co Ltd	新規な含窒素多糖体およびその製造方法
JP2604930B2 (ja)	1990-12-14	1997-04-30	株式会社ディ・ディ・エス研究所	ヒアルロン酸およびコンドロイチン誘導体
CA2059693C (en) *	1991-01-28	2003-08-19	Peter J. Kniskern	Polysaccharide antigens from streptococcus pneumoniae
JPH0784481B2 (ja)	1991-02-21	1995-09-13	株式会社デイ・デイ・エス研究所	カルボキシメチルマンノグルカン及びその誘導体
JP3359955B2 (ja)	1992-07-16	2002-12-24	第一製薬株式会社	抗腫瘍剤
ES2149867T3 (es)	1993-02-26	2000-11-16	Drug Delivery System Inst Ltd	Derivados de polisacaridos y soportes para farmacos.
JPH0784481A (ja)	1993-06-26	1995-03-31	Ricoh Co Ltd	画像形成装置
SG50747A1 (en)	1995-08-02	1998-07-20	Tanabe Seiyaku Co	Comptothecin derivatives
TW527183B (en)	1996-06-06	2003-04-11	Daiichi Seiyaku Co	Drug complex
US6299881B1 (en) *	1997-03-24	2001-10-09	Henry M. Jackson Foundation For The Advancement Of Military Medicine	Uronium salts for activating hydroxyls, carboxyls, and polysaccharides, and conjugate vaccines, immunogens, and other useful immunological reagents produced using uronium salts

1997
- 1997-05-31 TW TW086107456A patent/TW409058B/zh not_active IP Right Cessation
- 1997-06-05 EP EP97924326A patent/EP0955064B1/de not_active Expired - Lifetime
- 1997-06-05 CA CA002257233A patent/CA2257233A1/en not_active Abandoned
- 1997-06-05 ID IDP971929A patent/ID17243A/id unknown
- 1997-06-05 AT AT97924326T patent/ATE273716T1/de not_active IP Right Cessation
- 1997-06-05 ES ES97924326T patent/ES2229355T3/es not_active Expired - Lifetime
- 1997-06-05 DK DK97924326T patent/DK0955064T3/da active
- 1997-06-05 DE DE69730352T patent/DE69730352T2/de not_active Expired - Lifetime
- 1997-06-05 US US09/147,341 patent/US6291671B1/en not_active Expired - Fee Related
- 1997-06-05 JP JP50042298A patent/JP4137184B2/ja not_active Expired - Fee Related
- 1997-06-05 AU AU29788/97A patent/AU723442B2/en not_active Ceased
- 1997-06-05 PT PT97924326T patent/PT955064E/pt unknown
- 1997-06-05 EA EA199900002A patent/EA001897B1/ru not_active IP Right Cessation
- 1997-06-05 WO PCT/JP1997/001915 patent/WO1997046261A1/ja not_active Ceased
- 1997-06-05 CN CNB971971153A patent/CN1227034C/zh not_active Expired - Fee Related
1998
- 1998-12-04 NO NO19985667A patent/NO323626B1/no unknown

Also Published As

Publication number	Publication date
AU2978897A (en)	1998-01-05
ID17243A (id)	1997-12-11
ATE273716T1 (de)	2004-09-15
EA199900002A1 (ru)	1999-08-26
WO1997046261A1 (fr)	1997-12-11
NO985667D0 (no)	1998-12-04
NO985667L (no)	1999-02-04
EP0955064A4 (de)	2000-12-06
NO323626B1 (no)	2007-06-18
US6291671B1 (en)	2001-09-18
AU723442B2 (en)	2000-08-24
DE69730352D1 (de)	2004-09-23
CN1227500A (zh)	1999-09-01
CA2257233A1 (en)	1997-12-11
EA001897B1 (ru)	2001-10-22
EP0955064B1 (de)	2004-08-18
TW409058B (en)	2000-10-21
JP4137184B2 (ja)	2008-08-20
DE69730352T2 (de)	2005-09-08
DK0955064T3 (da)	2004-12-06
EP0955064A1 (de)	1999-11-10
PT955064E (pt)	2004-10-29
CN1227034C (zh)	2005-11-16

Publication	Publication Date	Title
ES2229355T3 (es)	2005-04-16	Procedimiento para la fabricacion de complejos medicamentosos.
ES2229354T3 (es)	2005-04-16	Complejos medicamentosos polialcohol-alquildextrano.
JP4560210B2 (ja)	2010-10-13	薬物複合体
JPWO1997046260A1 (ja)	1999-07-21	薬物複合体
JPWO1997046261A1 (ja)	1999-07-21	薬物複合体の製造方法
KR100387191B1 (ko)	2003-10-04	캄프토테신유도체
JPWO1999061061A1 (ja)	2002-11-12	薬物複合体
EP0640622B1 (de)	2000-08-09	Polysaccharidderivat und wirkstoffträger
JP4420472B2 (ja)	2010-02-24	薬物複合体
ES2371865T3 (es)	2012-01-10	Conjugados de hidroxialquilalmidón-principio activo.
US20040192644A1 (en)	2004-09-30	DDS compound and method for measurement thereof
AU4094300A (en)	2000-11-17	Amplification of folate-mediated targeting to tumor cells using polymers
JPWO1997038727A1 (ja)	1999-05-25	薬物複合体
JPH1192405A (ja)	1999-04-06	薬物複合体
ES2697250T3 (es)	2019-01-22	Conjugados para la protección de sustancias con efecto nefrotóxico
US8642555B2 (en)	2014-02-04	Prodrugs
KR100481434B1 (ko)	2006-10-24	약물복합체의제조방법
JP5189243B2 (ja)	2013-04-24	薬物複合体および薬物送達用担体
JP2002030002A (ja)	2002-01-29	薬物複合体